Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea 2

Transcription

1 Official Journal of Korean Continence Society / Korean Society of Urological Research / The Korean Children s Continence and Enuresis Society / The Korean Association of Urogenital Tract Infection and Inflammation pissn eissn einj.org Mobile Web NEUROUROLOGY JOURNAL INJINTERNATIONAL Original Article pissn eissn Clinical Significance of Periurethral Calcification According to the Location in Men With Lower Urinary Tract Symptoms and a Small Prostate Volume Jang Hee Han 1, Joo Yong Lee 2, Jong Kyu Kwon 2, Jong Soo Lee 1, Kang Su Cho 1 1 Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea 2 Department of Urology, Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea Purpose: To assess the impact of periurethral calcification (PUC) according to its location on uroflowmetric parameters and urinary symptoms in patients with small prostate volume (PV). Methods: Records were obtained from a prospectively maintained database of first-visit men with lower urinary tract symptoms (LUTS). Patients whose PV was >30 ml were excluded to elucidate more clearly the impact of PUC on LUTS. A total of 539 patients were enrolled in the study. The prostatic urethra was examined by transrectal ultrasonography for PUC, and the location of PUC was divided into 3 areas (proximal, mid, and distal). Results: The characteristics according to the location of PUC were compared using a 1-way analysis of variance test. The International Prostate Symptom Score (), postmicturition symptoms, and overactive bladder symptom score (OABSS) differed significantly among the groups. In the propensity score matching analysis, the proximal- and distal-puc groups did not have a significantly different urinary flow rate or symptom score when compared to their matched control groups. However, the mid-puc group had significantly worse urinary symptoms than its matched control group (total [P=0.001], voiding symptoms [P =0.002], storage symptoms [P =0.041], and OABSS [P =0.015]). The peak urinary flow rate was also lower in the mid-puc group with borderline significance (P =0.082). On multivariate linear regression analysis, mid-puc was independently associated with and OABSS (P=0.035 and P=0.011, respectively). Conclusions: Only mid-puc was associated with symptom severity in men with LUTS and a small PV. Our findings suggest that mid-puc could be a potential causal factor of LUTS, and the midportion of the prostatic urethra might play a pivotal role in the process of micturition. Keywords: Urethra; Prostatic hyperplasia; Lower urinary tract symptoms; Calculi; Inflammation Research Ethics: The study was performed in accordance with applicable laws and regulations, good clinical practices, and ethical principles as described in the Declaration of Helsinki. This study protocol was approved by the Institutional Review Board of Gangnam Severance Hospital (approval number: ). Written informed consent was obtained from all subjects. Conflict of Interest: No potential conflict of interest relevant to this article was reported. INTRODUCTION Lower urinary tract symptoms (LUTS) are known to be closely Corresponding author: Kang Su Cho Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea kscho99@yuhs.ac / Tel: / Fax: Submitted: September 29, 2016 / Accepted after revision: November 29, 2016 related to benign prostatic enlargement, benign prostatic obstruction (BPO), and benign prostatic hyperplasia (BPH). Accordingly, the static prostate enlargement determined by the This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2017 Korean Continence Society

2 Han, et al. Urethral Calcification With Urinary Symptoms INJ tone of the prostate and dynamic alpha-receptor-mediated smooth muscle tension are regarded as 2 major components connected to male LUTS [1]. However, in clinical practice, approximately half of LUTS patients have a relatively small prostate (30 ml or less) [2] and undoubtedly have a weaker correlation with those volume factors. Moreover, urodynamic findings showed that only half of the patients demonstrated bladder outlet obstruction in LUTS patients with a small prostate volume (PV), indicating the heterogeneity of this disease [3]. For this reason, several anatomical prostatic factors, such as the transitional zone index (TZI) and prostatic urethral angle (PUA), rather than simple volume parameters, have been investigated [4,5]. Male LUTS has a multifactorial etiology, and, recently, a third major hypothetical factor has been proposed, prostatic inflammation [1]. In particular, inflammation of the periurethral area, which ultimately induces periurethral fibrosis, could maximize induction of LUTS [6]. Although the etiology of prostatic calcification remains unclear, calcification of the urethra can, similar to other tissues, result in urethral stiffness [7,8]. Based upon this theoretical hypothesis, we have previously demonstrated the significant impact of periurethral calcification (PUC) on LUTS. To more clearly elucidate the impact of PUC on LUTS, the volume factor was purely confined in this study (PV 30 ml). Herein, we evaluated the association between PUC, urinary symptoms, and uroflowmetric measurements with a small PV and further analyzed the clinical impact of PUC according to its location (proximal, mid, or distal) on the prostatic urethra. MATERIALS AND METHODS Patient Cohort This study is a retrospective analysis of a prospectively maintained database of male patients with LUTS/BPH who had their initial visit at our outpatient clinic between April 2010 and April During this period, 1,199 patients were registered in our database. A detailed medical history was obtained for patients aged 40 to 80 years after excluding the following conditions that are potential LUTS inducing factors: (1) clinically apparent bladder or prostate cancer, (2) neurologic disease that could influence voiding symptoms, (3) uncontrolled diabetes mellitus, (4) history of a previous lower urinary tract surgery, (5) history of radiotherapy to the pelvis, and (6) urinary tract infections. A total of 1,030 patients were initially enrolled, and those with a total prostate volume (TPV) >30 ml were excluded. Finally, 539 patients were eligible for the final analysis. Good Clinical Practice Protocols The study was performed in accordance with applicable laws and regulations, good clinical practices, and ethical principles as described in the Declaration of Helsinki. This study protocol was approved by the Institutional Review Board of Gangnam Severance Hospital (approval number: ). Written informed consent was obtained from all subjects. Assessment of Urinary Symptoms and Uroflowmetric Measurements LUTS were evaluated using the International Prostate Symptom Score (), quality of life score, and overactive bladder symptom score (OABSS). The total was subcategorized into voiding, storage, and postmicturition symptom scores. For uroflowmetric measurements, maximum urinary flow rate (Qmax) and postvoid residual volume (PVR) were evaluated. Both uroflowmetric and PVR measurements were repeated if the voided volume was <125 ml. The assessment was made using Bluetooth uroflowmetry (Urodyn+; Mediwatch Ltd., Rugby, UK) and a bladder scanner (BioCon-500; MCube Technology Co., Ltd, Seoul, Korea). Assessment of Prostatic Anatomical Factors Transrectal ultrasonography (TRUS) was performed on all subjects (Prosound Alpha 5 SV, Hitachi Aloka Medical, Ltd., Tokyo, Japan [between April 2010 and November 2012]; Pro Focus 2202 Ultrasound System, BK-Medical, Herlev, Denmark [between December 2012 and April 2013]). TPV and transitional zone volume (TZV) were measured using the prolate ellipsoid formula (height width length π/6). The TZI was calculated according to the formula, TZI=TZV/TPV [9]. Prostatic calculi were viewed and scored in both axial and sagittal planes. Two investigators (JHH and JKK) independently determined the degree of prostatic calculi. Disagreement between the 2 investigators was resolved by a discussion with another investigator (KSC). The prostatic urethra was examined along the midsagittal plane. PUC was assessed for all of the sagittal images taken serially on TRUS, and we defined PUC as prostatic calcification that is within 2 mm of the prostatic urethra on the sagittal view of TRUS [10]. According to the classical definition demonstrated by Harada et al. [11], prostatic calcification demonstrating a burden or mass along the prostatic 221

3 INJ Han, et al. Urethral Calcification With Urinary Symptoms A B C D Fig. 1. Representative images of the 3 groups of periurethral calcification (PUC) according to their location on the midsagittal plane during transrectal ultrasonography. Midsagittal plane demonstrating the trace of the urethra without PUC (A), proximal PUC (B), mid-puc (C), and distal PUC (D). urethra was considered to be a clinically significant PUC, while the absence of or a small solitary calcification was considered to be an insignificant PUC. Overall PUC was determined based on the proportion of the urethra with significant calcification to the entire prostatic urethral length. The location of the PUC was divided into 3 consecutive nonoverlapping periurethral areas (proximal 1/3, middle 1/3, and distal 1/3) (Fig. 1). Statistical Analysis A 1-way analysis of variance (ANOVA) test was applied to compare the clinical characteristics of the 3 different PUC groups according to the location of the PUC. To clarify our comparisons, we targeted the patients that had PUC only in one location (proximal PUC only, mid-puc only, or distal PUC only). Using a propensity score matching analysis, the volume factor (TPV), age, and voided volume were matched, and each PUC group was sequentially compared to their matched control group using a paired t-test. All statistical analyses were performed using R software (version 3.0.3, R Foundation for Statistical Computing, Vienna, Austria; org). A P-value <0.05 was considered statistically significant, and all statistical tests were 2-sided. RESULTS As the result of interobserver reliability measurement, we recorded intraclass correlation coefficients for a PUC of (95% confidence interval, ), which indicates an excellent reliability. In terms of the patient baseline characteristics, the mean patient age was ±10.00 years, and the mean TPV and mean TZV were 23.05±4.12 and 9.71±2.88, respectively. On the midsagittal plane, overall PUC was classified into 3 groups. The numbers of patients with no, mild, and moderate to severe PUC were 351 (65.1%), 126 (23.4%), and 62 (11.5%), respectively. Regarding the distribution of PUC location, the number of patients in the proximal-, mid-, and distal-puc groups were 79 (14.7%), 124 (23.0%), and 69 (12.8%) (Table 1). We included 117 out of 539 patients (21.7%) who had only one location with PUC in the 1-way ANOVA test. The proximal-puc only (p-puc), mid-puc only (m-puc), and distal- PUC only (d-puc) groups were composed of 35, 63, and 19 patients, respectively. The 3 groups significantly differed in the 222

4 Han, et al. Urethral Calcification With Urinary Symptoms INJ Table 1. Clinical features of subjects (n=539) total, postmicturition symptoms, and OABSS, and the m- PUC group displayed the worst symptom scores in all fields, followed by the p-puc and d-puc groups. for the m- PUC group was 19.3 ±7.5, compared to 16.5 ±6.0 and 14.7 ±7.2 for the p-puc and d-puc groups, respectively (P=0.026). Postmicturition symptoms were 3.0±1.6 vs. 2.3±1.5 and 2.1±1.4, respectively (P=0.016). OABSS was 5.9±3.8 vs. 4.1±3.3 and 3.8± 2.1, respectively (P =0.017). There were no differences in the mean patient age or total PV among the three groups (Table 2). Propensity score matching analysis was performed for each group (p-puc, m-puc, and d-puc). Neither the p-puc or d- PUC groups demonstrated any significant impact on urinary symptoms or Qmax when compared to their matched control Value Age (yr) 60.03±10.00 Comorbidities Hypertension Diabetes mellitus 179 (33.2) 91 (16.9) Serum prostate-specific antigen (ng/ml) 1.29± ± ± ± ± ±1.11 OABSS 4.54±3.20 Uroflowmetry Qmax (ml/s) Voided volume (ml) Postvoid residual volume (ml) Prostate volume parameters prostate volume (ml) Transitional zone volume (ml) Transitional zone index Prostatic calcification Overall periurethral calcification None Mild Moderate to severe Location of periurethral calcification a) Proximal periurethral calcification Mid periurethral calcification Distal periurethral calcification 15.25± ± ± ± ± ± (65.1) 126 (23.4) 62 (11.5) 79 (14.7) 124 (23.0) 69 (12.8) Values are presented as mean±standard deviation or number (%)., International Prostate Symptom Score; OABSS, overactive bladder symptom score; Qmax, maximum urinary flow rate. a) A number of patients have been counted multiple times. group (Tables 3, 4). However, the m-puc group displayed significantly worse urinary symptoms than its matched control group ( [19.3 ±7.5 vs ±6.8, P =0.001], voiding symptoms [8.7 ±4.0 vs. 7.3 ±3.6, P =0.002], storage symptoms [7.5±3.5 vs. 6.4±3.3, P=0.041], and OABSS [5.9±3.8 vs. 4.2± 3.2, P =0.015]). Qmax was also lower in the m-puc group, with borderline significance (13.7±5.3 and 15.7±7.9, P=0.082) (Table 5). To confirm the independent clinical power of PUC, we performed univariate and multivariate linear regression analysis following propensity score matching analysis. For the multivariate model, variables proven significant in univariate analysis were taken into account. Multivariate linear regression analysis showed age, TZI, and m-puc significantly affected total (P=0.002, P=0.016, and P=0.035, respectively). For the OABSS, only age and m-puc were independently correlated (P<0.001 and P=0.011, respectively) (Table 6). DISCUSSION Male LUTS associated with a small PV represents approximately half of the total LUTS patients [2]. This ratio was also consistent with our data (539 of 1,030, 52.3%). Because the number of LUTS patients has increased over time, there have been several efforts to search for the significant prostatic anatomical parameters capable of predicting male LUTS, such as intravesical prostatic protrusion, TZI, presumed circle area ratio, peripheral zone thickness, and PUA. However, despite the high proportion of patients that have a small PV (<30 ml), only PUA and TZI have been shown to be independent factors affecting LUTS in this group [4,5]. LUTS in patients with a small PV is being highlighted due to the difference in its characteristics compared to those of general LUTS/BPH. Small PV LUTS patients are not likely to have BPO. The classical dynamic and static components of the prostate cannot explain the exact pathophysiology of small PV LUTS. The 5-alpha-reductase inhibitor finasteride has been shown in large cohort studies to have unsatisfactory results in small PV patients [12]. Alpha blockers play a role in reducing dynamic obstruction; however, outcome data is variable regarding small PV, making achieving a reliable assessment of the effects of medical treatments more difficult [13]. We focused on prostatic inflammation in small PV. For general LUTS/BPH, prostatic inflammation in a previous study was correlated with symptomatic progression, risk for urinary 223

5 INJ Han, et al. Urethral Calcification With Urinary Symptoms Table 2. Comparisons of clinical features according to location of periurethral calcification (PUC) (n=117) Proximal-PUC (n=35) Mid-PUC (n=63) Distal-PUC (n=19) P-value Age (yr) 62.0± ± ± ± Serum prostate-specific antigen (ng/ml) 1.2± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.0 OABSS 5.0± ± ± ± Uroflowmetry Qmax (ml/s) Voided volume (ml) Postvoid residual volume (ml) Prostate volume parameters prostate volume (ml) Transitional zone volume (ml) Transitional zone index 14.0± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.1 Values are presented as mean±standard deviation., International Prostate Symptom Score; OABSS, overactive bladder symptom score; Qmax, maximum urinary flow rate. Table 3. Matched cohorts of proximal periurethral calcification (PUC) present vs. absent groups using propensity scores (n=70) Matched Cohort Proximal PUC (-) (n=35) Proximal PUC (+) (n=35) P-value Age (yr) 62.0± ± ± prostate volume (ml) 22.7± ± ± Transitional zone volume (ml) 9.4± ± ± Transitional zone index 0.4± ± ± Qmax (ml/sec) 14.2± ± ± Voided volume (ml) 279.6± ± ± Postvoid residual volume (ml) 28.3± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.0 OABSS 4.7± ± ± Values are presented as mean±standard deviation. Qmax, maximum urinary flow rate;, International Prostate Symptom Score; OABSS, overactive bladder symptom score retention, and the need for surgery [14]. Complete understanding of the inflammatory process and its pathogenesis is still in progress; however, inflammation is emerging as the new targeted process for male LUTS [15]. Within the prostate s anatomic structure, inflammation of the periurethral region, leading to periurethral fibrosis, was recently highlighted as a LUTS-inducing factor [6,16-18]. Cantiello et al. [19] assessed periurethral tissues from radical prostatectomy specimens and suggested that fibrotic changes in periurethral prostatic tissues induced by prostate inflammation may eventually promote urethral stiffness and LUTS. Kim et al. [16] tested the association between prostate elasticity and LUTS with a novel palpation system (In

6 Han, et al. Urethral Calcification With Urinary Symptoms INJ Table 4. Matched cohorts of distal periurethral calcification (PUC) present vs. absent groups using propensity scores (n=38) Matched Cohort Distal PUC (-) (n=19) Distal PUC (+) (n=19) P-value Age (yr) 62.8± ± ± prostate volume (ml) 21.4± ± ± Transitional zone volume (ml) 9.3± ± ± Transitional zone index 0.4± ± ± Qmax (ml/sec) 14.1± ± ± Voided volume (ml) 240.1± ± ± Postvoid residual volume (ml) 19.3± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.0 OABSS 4.3± ± ± Values are presented as mean±standard deviation. Qmax, maximum urinary flow rate;, International Prostate Symptom Score; OABSS, overactive bladder symptom score. Table 5. Matched cohorts of mid-periurethral calcification (PUC) present vs. absent groups using propensity scores (n=126) Matched Cohort Mid-PUC (-) (n=63) Mid-PUC (+) (n=63) P-value Age (yr) 61.4± ± ± prostate volume (ml) 24.1± ± ± Transitional zone volume (ml) 10.5± ± ± Transitional zone index 0.4± ± ± Qmax (ml/sec) 14.7± ± ± Voided volume (ml) 257.9± ± ± Postvoid residual volume (ml) 30.3± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.1 OABSS 5.1± ± ± Values are presented as mean±standard deviation. Qmax, maximum urinary flow rate;, International Prostate Symptom Score; OABSS, overactive bladder symptom score denter) and showed that prostate elasticity was independently associated with voiding symptoms. Based on these studies, periurethral fibrosis can be assumed to be a cause of LUTS through decreased urethral flexibility while compromising the ability of the prostatic urethra to enlarge to adequately accommodate urinary flow during micturition [10,19]. Prostatic calcification has a pathological connection with prostatic inflammation and fibrosis. The etiology of prostatic calcification is not yet fully understood; however, studies at the molecular level have shown that calcifications induced by inflammation generate a microenvironment that drives more inflammatory change, characterized by lymphocyte infiltration, 225

7 INJ Han, et al. Urethral Calcification With Urinary Symptoms Table 6. Multivariate linear regression analysis of prostatic parameters for and OABSS International Prostate Symptom Score Overactive bladder symptom score Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis Standardized coefficient β P-value Standardized coefficient β P-value Standardized coefficient β P-value Standardized coefficient β P-value Age < < <0.001 TPV TZV TZI p-puc m-puc d-puc , International Prostate Symptom Score; OABSS, overactive bladder symptom score; TPV, total prostate volume; TZV, transitional zone volume; TZI, transitional zone index; p-puc, proximal periurethral calcification; m-puc, mid periurethral calcification; d-puc, distal periurethral calcification. cytokine activation, and release of reactive oxygen species [20-22]. Prostatic calcification is not synonymous with prostatic fibrosis, but chronic inflammation can eventually lead to fibrosisrelated calcification, a proven phenomenon in other tissues [23-25]. If inflammation induces urethral calcification, this process can, as shown in other tissues, affect urethral stiffness [7,8]. In this study, PUC was proposed as an independent risk factor for male small PV LUTS. Notably, this is the first trial to assess PUC according to its location and to demonstrate that PUC is independently associated with worse urinary symptom scores in a small PV. We previously reported that overall PUC was associated with Qmax, total, and storage symptoms in TPV [10]. However, in the current study overall PUC was only associated with the Qmax when limited to small PV (data not shown). Taking these findings together, we can deduce that periurethral inflammation has a more synergistic effect on male LUTS if accompanied by a larger prostate. The degree of overall PUC according to TPV in those with a small PV was similar (none, mild, moderate to severe: 63.5%, 22.6%, and 13.9% vs. 65.1%, 23.4%, and 11.5%). The mean age difference between the 2 trials was approximately 2 years, and the mean PV difference was approximately 10 g (i.e., the TPV group was older and had larger prostates). For the proximal PUC, we considered this presentation to be inflammation and fibrosis of the proximal prostatic urethra and bladder neck, which could hypothetically play a major role in micturition initiation. In clinical practice, primary bladder neck obstruction without BPH is related to a reduced flow rate and higher urinary symptom scores by disturbing bladder neck relaxation during the voiding phase. Its etiology varies, and one of the etiologies is known to be an inflammatory-induced fibrotic change [26,27]. However, in this study we failed to prove any clinical relevance of the p-puc group with the peak urinary flow rate or urinary symptoms. A future study should be undertaken to evaluate the potential relationship between bladder neck calcification and endoscopically proven bladder neck obstruction. Additionally, the d-puc group also failed to show any significant impact on the peak urinary flow rate or urinary symptom scores. In the one-way ANOVA test comparing the uroflowmetric measurements and urinary symptom scores among the 3 different PUC groups (p-puc, m-puc, and d-puc), the patient with distal-puc typically had the best outcomes compared to the p-puc and m-puc groups. From this result, conversely, we provisionally conclude that the distal portion of the prostatic urethra has a minimal role in the micturition process compared to the proximal and midportions. Distinct from the p-puc and d-puc groups, the m-puc group showed a significant impact on most of the urinary symptoms in patients with a small PV. There have been several studies demonstrating urethral movement during the voiding phase. Ukimura et al. [28] reported that the prostatic urethra is pulled upward in a ventral direction toward the pubic bone during voiding. This theory is consistent with PUA mechanics; the urethra tends to reduce its resistance by reducing the PUA by moving ventrally, consequently straightening the urethra. However, if the PUA remains high due to limited movement induced by PUC, energy loss proportional to the PUA could 226

8 Han, et al. Urethral Calcification With Urinary Symptoms INJ occur during micturition and could result in a decrease in urine velocity, consequently causing LUTS [4,29]. Theoretically, due to the mid-puc leading to midperiurethral fibrosis, the PUA could have a fixed tone, causing ineffective voiding, and ultimately causing LUTS. From the urethral dynamic mechanics proven above, we believe these significant findings regarding the mid-puc indirectly support the idea that the midportion of the prostatic urethra is a clinically important region with respect to male LUTS. However, our study has some limitations. First, this study included a small number of subjects; thus, further study with a larger cohort is needed to draw a more objective and concise conclusion regarding PUC in patients with a small PV. Although PUC, inflammation, and fibrosis are hypothetically mutually related, it remains unclear whether these 3 factors have the same impact on LUTS or not [10]. Studies on the differences in pathological prostatic tissue according to varying prostate PUC location are warranted. Regarding proximal PUC, further study is required to assess the relationship between the proximal-puc group and bladder neck fibrosis, accompanied by a pathological and mechanical analysis. Furthermore, a meticulous assessment of the dynamic movement of the urethra is still imperative, and additional controlled prospective studies regarding the effect of urethral stiffness on the 3-dimensional movement of the urethra should be described in future studies. In conclusion, only mid-puc was associated with urinary symptom severity in men with LUTS and a small PV. Our findings suggest that the mid-puc could be a potential causal factor of LUTS, and the midportion of the prostatic urethra might play a pivotal role in the process of micturition. REFERENCES 1. Nickel JC, Roehrborn CG, O Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol 2008;54: Overland GB, Vatten L, Rhodes T, DeMuro C, Jacobsen G, Vada K, et al. Lower urinary tract symptoms, prostate volume and uroflow in norwegian community men. Eur Urol 2001;39: Gomes CM, Nunes RV, Araújo RM, Sacomani CR, Trigo-Rocha FE, Bruschini H, et al. Urodynamic evaluation of patients with lower urinary tract symptoms and small prostate volume. Urol Int 2008;81: Kang DH, Lee JY, Hah YS, Chung DY, Lee DH, Cho KS. Correlation of prostatic urethral angle with the severity of urinary symptom and peak flow rate in men with small prostate volume. PLoS One 2014;9:e Choi J, Ikeguchi EF, Lee SW, Choi HY, Te AE, Kaplan SA. Is the higher prevalence of benign prostatic hyperplasia related to lower urinary tract symptoms in Korean men due to a high transition zone index? Eur Urol 2002;42: Rodriguez-Nieves JA, Macoska JA. Prostatic fibrosis, lower urinary tract symptoms, and BPH. Nat Rev Urol 2013;10: Forman JL, Kent RW. The effect of calcification on the structural mechanics of the costal cartilage. Comput Methods Biomech Biomed Engin 2014;17: Sekikawa A, Shin C, Curb JD, Barinas-Mitchell E, Masaki K, El- Saed A, et al. Aortic stiffness and calcification in men in a population-based international study. Atherosclerosis 2012;222: Kaplan SA, Te AE, Pressler LB, Olsson CA. Transition zone index as a method of assessing benign prostatic hyperplasia: correlation with symptoms, urine flow and detrusor pressure. J Urol 1995;154: Han JH, Kwon JK, Lee JY, Kang DH, Choi HC, Lee JS, et al. Is periurethral calcification associated with urinary flow rate and symptom severity in men with lower urinary tract symptoms-benign prostatic hyperplasia? A retrospective review. Urology 2015;85: Harada K, Igari D, Tanahashi Y. Gray scale transrectal ultransonography of the prostate. J Clin Ultrasound 1979;7: Kaplan SA, Lee JY, Meehan AG, Kusek JW; MTOPS Research Group. Long-term treatment with finasteride improves clinical progression of benign prostatic hyperplasia in men with an enlarged versus a smaller prostate: data from the MTOPS trial. J Urol 2011;185: Kaplan SA, McConnell JD, Roehrborn CG, Meehan AG, Lee MW, Noble WR, et al. Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater. J Urol 2006;175: Roehrborn CG. Definition of at-risk patients: baseline variables. BJU Int 2006;97 Suppl 2: Vela Navarrete R, Garcia Cardoso JV, Barat A, Manzarbeitia F, López Farré A. BPH and inflammation: pharmacological effects of Permixon on histological and molecular inflammatory markers. Results of a double blind pilot clinical assay. Eur Urol 2003;44: Kim KH, Ahn B, Lim SK, Han WK, Kim JH, Rha KH, et al. In

9 INJ Han, et al. Urethral Calcification With Urinary Symptoms denter study: associations between prostate elasticity and lower urinary tract symptoms. Urology 2014;83: Ma J, Gharaee-Kermani M, Kunju L, Hollingsworth JM, Adler J, Arruda EM, et al. Prostatic fibrosis is associated with lower urinary tract symptoms. J Urol 2012;188: Gharaee-Kermani M, Rodriguez-Nieves JA, Mehra R, Vezina CA, Sarma AV, Macoska JA. Obesity-induced diabetes and lower urinary tract fibrosis promote urinary voiding dysfunction in a mouse model. Prostate 2013;73: Cantiello F, Cicione A, Salonia A, Autorino R, Tucci L, Madeo I, et al. Periurethral fibrosis secondary to prostatic inflammation causing lower urinary tract symptoms: a prospective cohort study. Urology 2013;81: Shoskes DA, Lee CT, Murphy D, Kefer J, Wood HM. Incidence and significance of prostatic stones in men with chronic prostatitis/ chronic pelvic pain syndrome. Urology 2007;70: Gandaglia G, Briganti A, Gontero P, Mondaini N, Novara G, Salonia A, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int 2013;112: Ficarra V, Sekulovic S, Zattoni F, Zazzera M, Novara G. Why and how to evaluate chronic prostatic inflammation. Eur Urol Suppl 2013;12: Balin SJ, Wetter DA, Andersen LK, Davis MD. Calcinosis cutis occurring in association with autoimmune connective tissue disease: the Mayo Clinic experience with 78 patients, Arch Dermatol 2012;148: New SE, Aikawa E. Cardiovascular calcification: an inflammatory disease. Circ J 2011;75: Detlefsen S, Sipos B, Feyerabend B, Klöppel G. Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch 2005;447: Huckabay C, Nitti VW. Diagnosis and treatment of primary bladder neck obstruction in men. Curr Urol Rep 2005;6: Nitti VW. Primary bladder neck obstruction in men and women. Rev Urol 2005;7 Suppl 8:S Ukimura O, Iwata T, Ushijima S, Suzuki K, Honjo H, Okihara K, et al. Possible contribution of prostatic anterior fibromuscular stroma to age-related urinary disturbance in reference to pressure-flow study. Ultrasound Med Biol 2004;30: Cho KS, Kim JH, Kim DJ, Choi YD, Kim JH, Hong SJ. Relationship between prostatic urethral angle and urinary flow rate: its implication in benign prostatic hyperplasia pathogenesis. Urology 2008; 71: